1,2-naphthoquinone condensation products



Patented May 29, 1 951 1 V UNITED STATES PATENT OFFICE 1,2-NAPHTHOQUINONE CONDENSATION PRODUCTS Norbert Steiger, Nutley, N. J., assignor to H011- mann-La Roche Inc., Nutley, N. J., a corporation of New Jersey No Drawing. Application February 16, 1950, Serial No. 144,589

6 Claims. (Cl. 260-396) I I 2 The present invention relates to new derivabe varied over a wide range, for example, from tives of 1,2-dihydro-1,2-dioxo-naphthoquinones about 15 to 60 C. The reaction is usually comwhich can be represented by the following forplete in about 3-4 hours. When a 1,2-naphthomula: quinone-disulfonic acid is employed which con- 5 tains one of its sulfo groups in the 4-position, or salt thereof, then the compounds of Formula I 0 contain a sulfo group; that is, R, in Formula I R is a sulfo radical. Such compounds are generally soluble in water, whereas those which do not contain a sulfo group are generally insoluble in wa- R1 ter. Compounds of the invention are of interest wherein R is a member of the group consistin for their Chemotherapeutic p p mOIB p of hydrogen and a sulfo radical, R1 is a radical of ticularly as amebicidal and antiviral agents.

the group consisting of The diamine of Formula A where :L' is 0 is a --NH(C cHaS O2NH)S OzNHQ (NHS O2CoH4)=NH2 and known compound; namely, 4'-aminosulfanilanilide. Where :c is 1, 2, 3 and 4 or higher, the di- -NH(GH4S 0mm ,Q-(NHSO CflHi) 1,NHZ amines are new compounds, and can be prepared as illustrated by the following equation, which wherein :1: stands for 0, 1, 2, 3 or 4 and y for l, 2, 3 demonstrates the preparation of the diamine or 4; and the salts thereof. where a: is 1.

HZNQS mNHGNH, 20:5,0 ONHS0,C1

(II) (III) NaOH 01130 ONE-Q-SO NHQ-SMNH NHSO NH0 0 CH3 NrmcansomwQ-smimQmnsono noNn,

. v The compounds of Formula I can, in general, 4'-aminosulfanilanilide II is reacted with two be prepared by condensing a 1,2-naphthoquinonemoles of N-acetylsulfanilyl chloride (III, which 4-sulfonic acid or its alkali salts, i. e., the sodium will hereinafter be referred to for brevitys sake or potassium salt, with a diamine which can be 40 as ABC) to form p,p'bis-(p-acetoamidophenylrepresented by one of the following formulae: sulfonamido)benzenesulfonanilide IV, which is NH (C H4SO2NHpSO NH-Q-(NHSO C HiLNH (A) and then hydrolyzed with sodium hydroxide to form p,p'-bis (p aminophenylsulfonamido)benzenesulfonanilide V, which will hereinafter be referred NH;(C@H4S 021m ,Qmnsmmm) ,NHz (B) to as Tri.

By repeating the process on Tri with two moles of ASC, there is obtained p,p'-bis-[p-(p-aminophenylsulfonamido)phenylsulfonamidolbenzenewherein m and y have the same significance as sulfonanilide, the compound where an in Formula already assigned thereto. A is 2, which will herein be referred to as Penta. The condensation reaction is generally carried By repeating the process on Penta with two out in an aqueous medium, the diamines being moles of A80, there is obtained p,p'-bis-{p[pdissolved in an alkaline solution, such as aqueous (p aminophenylsulfonamido) phenylsulfonamisodium hydroxide or sodium carbonate, and the do] phenylsulfonamido}benzenesulfonanilide, the

resulting solution being added to an aqueous suscompound where a: in Formula A is 3, which will pension or solution of the 1,2-naphthoquinoneherein be referred to as Hepta. sulfonic acid or salt thereof, while stirring or By repeating the process on Hepta with two agitating. The temperature of the reaction may v50 moles of A50, there is obtained p,p'-bis-(p-{p- [p- (p amino'phenylsulfonamido)phenylsulfonamido] phenylsulfonamido}phenylsulfonamido) benzenesulfonanilide, the compound where a: in Formula A is 4, which will hereinafter be referred to as Nona.

It will be appreciated that by further repetition of the process other diamines of Formula A where H a: is greater than 4, can also be obtained.

The diamine of Formula B where y is 1 is a known compound; namely, N ,N '-p-phenylenebis-sulfanilamide. Where y is 2; 3, and 4 or higher the diamines are new compounds and be prepared as illustrated by the following equation, which demonstrates the preparation of the diamine where y is 2 (VI) lNaOH added in portions alternately to-'7-'00 grams of pyridine below 60 C. and stirred for 3 hours at 80 C. The reaction mixture was then poured into liters of ice water and 500 cc. of 36.5% hydrochloric acid. p,p' Bis [p-(p-acetamidophenylsul'fonamido) phenylsulfonamido] benzenesulfonanilide precipitated and was filtered, washe'd'with ice water and sucked dry. The com- "pound was hydrolyzed with a solution of 200 grams of sodium hydroxide in 1600 cc. of water by refluxing. for 4 hours. The hydrolyzed product was filtered and the filtrate neutralized at 15-25 C. with hydrochloric acid. After filtration, washing with water and drying, Penta was obtained as a white powder.

.omc ONHQ-S emuorms omm-Q-mus O CQHQ-NHS OQ-NHC 0 cm I (VIII) moles of ASC, there is obtained N ,N "-p-ph'en'ylene bis {N -[p-(p ammophenylsulfonamido) .phenylsulfonyl]sulfanilamide}, the compound where y in Formula B is 3,which will hereinafter be referred to as Hexa.

By repeating the process on Hexa with two moles of A50, there is obtainedN fN -p-phenylene bis [N {p (p-[p-ammophenylsulfon amidol phenylsulfonamido)phenylsulfonyla}sulfanilamidel the compound where -y in- Formula B is 4, which will hereinaftenbereferred to as'Oeta. It will be appreciated that by further repetition of the 'process'o't'her diamines "df'FormulaB wliere y is greater than 4can'be obtained.

The following examples will serve'to illustrate the preparation ofthe diamines of Formula A.

Tri

237 grams of "4"-aminosulfani1anilideand 450" grams of ASC were added in portions alternately to 450 grams of pyridine at below 70 C. The mixture was then heated for 2 hours 'to80""C. and the resulting syrupy melt poured into 5 liters of ice water and 325"cc.-of concentrated (365%) hydrochloric acid. -p,p Bis--(p-acetamidophenylsul'fonamido) benzenes'ulfonanilide pre'cipit'ate'd and was filtered, washed with ice water and sucked dry. The compound was then hydrolyzed with a solution of 160 grams of sodiumfhydrox'ide in 1400 cc. ofwater at reflux for 4 hours. The hydrolyzed product was filtered at 80 C., 1 diluted with 2000 grams of ice and. one liter of water, and neutralized with 300 cc. of 36.5% hydrochloric acid. The Tri thus obtained wasfiltered, washed with ice water and dried. Upon crystallization from methanol-benzene Tri meltedat 148 C.

Penta 550 grams of mend-475 gramsof 'ASCwere EXAMPLE (2 H epta 6'70 grams of Penta and 400 grams of ASC were added 'in portions alternately to 800 grams of pyridine below 60 C. and heated for 3 hours at C. The reaction mixture was then poured in 10 liters of ice water and 500 cc. of 36.5% hydrochloric acid. p,p -Bis-{p- [.p- (p-acetamidophenylsulfonami'do) phenylsul'fonamidolpheny1sulfonamido}- benzenesulfonanilide which formed, was filtered and washed with water "and; suckedidry. It was hydrolyzed with a solution"of"240gramsofsodium hydroxide in 2200 00. of water at vreflux for 4 hours. The hydrolyzed product was filtered and the filtrate was neutralized at '15 to "25 'C. with hydrochloric acid. Themeutralized product was filtered, washed with water and dried, yielding :Hepta as a white powder.

EXAMPLE D Nona 853 grams of I-Iepta and 400 grams of ASC were added in portions alternately to 900g rains of pyridine below 60 C. The mixture was then stirred for 3 hours at-8l)"--C., poured into 10 liters of ice and water and neutralized with hydro- :ChlOfiC acid to purple-Congo reaction. -p,p-Bis- (p {p [p (p acetamidophenylsulfonamido) phenylsulfonamido l-phenylsulfonamido}phenyl sulfonamidoi benzenesulfonanilide thus formed was filtered, washed .with water and suckeddry. It was hydrolyzed with a solution made up'of 300 grams of sodium hydroxide and 2800 cc. of water at the boil for "5 hours. The hydrolyzed product was filtered -at 80C., the filtrate was neutralized with hydrochloric acid at 20 C., and the neutralized product was filtered, washed with water anddried, yielding Nona as a white powder.

The following examples will serve to illustrate the preparation of diamines of-Formula B.

Tetra 118 grams of N ',N p-phenylene-bis-sulfanilamide and grams of A SC were "added in portions alternately to 400-grams of pyridinebelow 40 C. and the mixture heated for 1 hour with 2,554,543 i 6 agitation at 70 C., then poured into a solution of der. The compound was filtered, washed with 5000 cc. of ice water and 350 cc. of 36.5% hydrowater and sucked dry. It was heated to the boil chloric acid. N ,N -p-phenylene bis [N -(pfor 4 hours with 1000 cc. of a sodium hyacetamidophenylsulfonyl)sulfanilamidelwhich droxide solution. The hydrolyzed product was precipitated was filtered, washed with water and 5 filtered hot and neutralized with hydrochloric sucked dry. The compound was hydrolyzed with acid at -25 C. Octa precipitated. It was fila solution made up of 100 grams of sodium hytered, washed with cold water and dried, wheredroxide and 800 cc. of water at 100 C. for 4 hours. upon it was obtained as a white powder. 10 grams of charcoal and 10 grams of a filter aid The following examples will serve to illustrate were added at 80 C. and the solution was filtered. 10 the preparation of the compounds of Formula I.

EXAMPLE 1 o l NH(C H S0zNH)4SOzNH-G-(NHSOgOsHOANH, The filtrate was neutralized with hydrochloric 46 grams of Nona were dissolved in a solution acid at 20-25 C. After drying, Tetra was obmade up of 26 cc. Of a 40% sodium hydroxide tained as awhite powder, M. P. 220 C. solution and 200 cc. of water at 70 C. and the XAMPLE g 1 solution filtered. The filtrate was dropped into a E F solution of grams of 1,2-naphthoquinone-4- Hem potassium sulfonate in 800 cc. of water and 10 cc. 110 grams of Tetra and 90 grams of ASC were o acetic d at om p a ure w h a itaadded in portions alternately to 300 cc. of pyrition. The stirring was continued for 6 hours.

dine below 40 C. and the reaction mixture then 0 The prec p e Which formed Was filtered y heated to 70 C. for 3 hours. It was then poured 3 suction and washed with 2 liters of water, sucked into a solution made up of 3000 cc. of ice water y d then dried a yielding e 00mand 300 cc. of 36.5% hydrochloric acid. N ,N p d f the above f ula. T mp und is of p-phenylene bis {N [p-(p-acetamidophenylpinkish color, insoluble in Water but soluble in sulfonamido) phenyl-sulfonyl]sulfanilamide} pre- 35 hot 80% ethanol. It is soluble in dilute sodium cipitated and was filtered, washed with water and hydroxlde, glvmg an Orange-brown solution.

EXAMPLE 2 NaOaS 1 in admonish-Gsown-Q-mnsowsnpnm sucked dry. The compound was hydrolyzed with 22.5 grams of Nona were dissolved in a solution a solution made up of 100 grams of sodium hymade up of 200 cc. of water and 8 grams of sodidroxide and 900 cc. of Water at 100 C. for 4 hours. um carbonate at 90 C. and the solution was The hydrolyzed product was filtered hot and the filtered hot. The filtrate was dropped into asolufiltrate neutralized with hydrochloric acid wheretion of 20 grams of 1,2-naphthoquinone-4,6-di upon Hexa precipitated in crystalline form. When potassium disulfonate in 300 cc. of water. After crystallized from methanol-benzene, Hex-a melted stirring for 30 minutes there were added 10 cc.

at 227 C. with decomposition. of hydrogen peroxide (30%). After further XHIPLIE stirring for 1 hour, 5 grams of sodium carbonate E G were added and the stirring continued for 6 hours. The condensation product was obtained 93 grams of Hexa and grams of A50 were s a r ip tat f sli y ddish color. The added in portions alternately to 300 cc. of pyripreolpitate Was filtered and washed with ice wadine below 60 C. The reaction medium was then t Sucked y and finally dried at 0, yieldheated for 3 hours at 70-80 C. and then poured 60 mg the Compound of the above formula. The into a solution made up of 4000 cc. of ice water compound is of reddish color and is soluble in and 300 cc. of 36.5% hydrochloric acid. N ,N hot water.

' EXAMPLE 3 NBOJS O p nmoflmsomnnQ-somnQqrmsmQmmn.

p-phenylene-bis-[N -{p-(p-[p-acetamidophenyl- '22 grams of Nona were dissolved in a solution sulfonamidolphenylsulfonamido)phenylsulfonyl} made of 250 cc. of water and 8 grams of sodium sulfanilamide] precipitated aska white sandy powcarbonate at C. and the solution was filtered hot. The filtrate Was. dropped into: a solution. 7 of: 19 grams. of 1,2-naphthoquinone-4fl-dipotas-- sium disulfonate in 300 cc. of water. After stir- 1 ring for 30 minutes, 10 cc. of hydrogen'peroxide (30%). were added. After further stirring for 5 1 hour, 5 grams of sodium carbonate werev added ant-l the. stirring continuedfor 6 hours. A. reddish precipitate was obtained which. wasfiltered, washed with water, and. then dried at 80 vC., g yielding'the compound of. the above. formula- 10 The compound is of reddish color and is'soluble in hot water. grams of Octa were dissolved in a solution EXAMPLE 4 l IHGaHiSOzNHQ-SOzNH-Q-NHSOnOuHlNH;; 7 grams of Tri were dissolved in a solution made up of 10 cc; of 1 N sodiumhydroxide and made up of 70 cc. of water and 5 cc. of V l0 N 150 cc. of water and the resulting solution sodium hydroxide and-the resulting'solution-was dropped i t a luti of 15 grams of 1,2- dropped into a solut on of 12 grams of naphthoquinone-4-potassium sulfonate, 400 cc. naphthoqulnone'4'sodlmsu1f9nate m390' of of water, and 8 cc. of glacial acetic. acid. The Water and 4 of glacial acetic acld Wlth good reaction mixture'was stirred at room temperature agitation which was continued for 6 hours. The reddish precipitate which formed was filtered, washed and dried, yielding the compound. of the above formula. The compound is of reddish for 8 hours. The'precipitate which formedwas filtered and dried, yielding thev compound of, the above formula. The compound was obtained as color, insoluble in Water and soluble in l N sodia. pinkish DOWder insoluble in water but soluble um hydroxide solution. in aqueous sodium hydroxide solution.

EXAMPLE 5.

24 grams of Hepta were dissolvedin a solution" EXAMPLE 8 madeup of. 200 cc. of Water and 14 grams of 0 sodium carbonate and the resulting solution poured into a solution made up of 20 grams of 1.2- naphthoquinone-e,6-dipotassium disulfonate, 200 cc. of water and 10 grams of sodium acetate. The Naoas reaction medium was agitated for 8 hours at room temperature. The reddish precipitate which formed was filtered and dried, yielding the-compound of the above formula. The compound is 20 grams of Octa were dissolved in a solution a reddish powder, soluble in hot water. made up of 10 cc. of v10:.N sodium hydroxide and EXAMPLE 6 100 cc. of water and the resulting solution dropped into a solution made up of 20 grams of 1,2- 1 naphthoquinone-4,6-dipotassium disulfonate, 300 T cc; of'water, and-.8 cc. of glacial acetic acid. The

mixture was then stirred at. room temperature for. 8-hours. Theprecipitate which formed was filteredand dried, yielding the compound of the l above formula. The compound is a red powder Q and is soluble in hot water. 10 grams of 4-aminosulfani1anilide were dis- EXAMPLE 9 solved in a solution made up of 5 cc. of 10 N 0, sodium hydroxide and 100 cc. of water and the l resulting solution dropped into a solution of 20 -0 grams of 1,2-naphthoquinone-4-sulfonic acid in 400 cc. of water and 5 cc. of acetic acid with good agitation which was continued for 6 hours. The I precipitate which formed was filtered, washed NH(C H SO NH);(NHSo O HmNH and dried, yielding the compound of the above p formula. The compound isa red powder insoluble 14 grams of Tetra weredissolved in asolution in water andsoluble in 1 N sodium hydroxide. made up of 10 cc. of 10 sodium hydroxide 9 10 d and 100 cc. of water. The resulting solution was B, being a member of the group consistmg of dropped into a solution made up of 15 grams of hydrogen and a sulfo radical, and R1 bein a 1,2-naphthoquinone-4-sodium sulfonate and 6 cc. radi l of th ro consisting of of glacial acetic acid. The mixture was stirred at room temperature for 8 hours. The precipitate and which formed was filtered and dried, yielding the compound of the above formula. The compound is a red powder, insoluble in water, and

soluble in aqueous sodium hydroxide. NH CH4SOZNEFQWHSOMHOvNHz EXAMPLE 10 O a: being a member of the group consisting of 0, 1, 2, 3 and 4 and :1; being a member of the group consistin of 1, 2, 3 and 4, and the salts thereof.

2. The com ound which can be re resented b NH(CuH4SO1NH)a(NHSOzOMOaNH: the followingpformula. p y

NH(C H4SO NH) -SO;NHQ(NHSOzCaH4)4NH 20 grams of Hexa were dissolved in a solution 3. The compound which can be represented made up of 10 N sodium hydroxide and 150 cc. by the following formula:

' NH C9H4SOgNH)4-S@gNH-(NHSO2 0H4)4NH1 of water. The resulting solution was added to 4. The compound which can be represented by a solution made up of 20 grams of 1,2-naphthothe following formula;

Name

NH(CoH S0 NH)|SOaNHQ-(NHSO C HQ NH; quinone-4-potassium sulfonate, 400 cc. of water The c mp un Whi h a b r pr y and 6 cc. of acetic acid. The reaction mixture the following formula: was stirred at room temperature for 8 hours. 0 The precipitate which formed was filtered and 1 dried, yielding the compound of the above 0 formula. The compound is a red powder and is insoluble in water.

I claim:

1. A comp un which c n be repr y NmconisomnpQmnsmomomm the following formula:

6. The compound which can be represented by the following formula:

7o nmmmsomnp-Qqmrs olmnomm NORBERT STEIGER. No references cited. 

1. A COMPOUND WHICH CAN BE REPRESENTED BY THE FOLLOWING FORMULA: 